PARALLAX findings underscore HFpEF challenges

The angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan brought significantly decreased plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels compared with both standard renin angiotensin system (RAS) inhibitor treatment and placebo in heart failure patients with preserved ejection fraction (HFpEF; >40%), according to results from the PARALLAX study. Sacubitril/valsartan did not, however, significantly improve 6-minute walk distance or quality of life.

The results were published in JAMA.

“Sac/Val was tested against an ARB (valsartan) in PARAGON-HF, but many patients are treated with an [angiotensin-converting enzyme inhibitor] ACEI or no [renin angiotensin system inhibitor] RASI at all. We wanted to define the treatment effect of Sac/Val against standard medications for risk factor control: [angiotensin II receptor blockers] ARBs, ACEI, or no RASI. Exercise capacity is largely impaired in HFpEF, but the effects of Sac/Val on exercise capacity are unknown. We tested the effects of Sac/Val against individual comparator groups on submaximal exercise capacity,” lead author Burkert Pieske, MD, of Charité University Medicine, Campus Virchow Klinikum, Berlin, Germany, told BreakingMED, in an email correspondence.

For their randomized, double-blind, parallel group study, Pieske and colleagues enrolled 2,240 patients (mean age: 72.6 years; 50.7% women) with heart failure and an LVEF >40%, elevated NT-proBNP, structural heart disease, and reduced quality of life to treatment with either sacubitril/valsartan (97 mg/103 mg twice daily) or a comparator (enalapril [target dose: 10 mg], valsartan [target dose: 160 mg], or placebo [no RAS inhibitor stratum]).

The primary endpoints of the study were change from baseline to week 12 in NT-proBNP levels and 6-minute walk distance at week 24. Secondary endpoints included changes in quality-of-life measures and New York Heart Association (NYHA) level at 24 weeks.

Median baseline NT-proBNP levels in patients treated with sacubitril/valsartan were 786 pg/mL, and 760 pg/mL in patients in the control group. Median BMI was 30.4, indicating that most patients were overweight or obese.

After 12 weeks of treatment, significantly greater reductions in NT-proBNP levels were seen in patients treated with sacubitril/valsartan compared with those in the comparator group (adjusted geometric mean ratio to baseline: 0.82 versus 0.98 pg/mL, respectively [adjusted geometric mean ratio: 0.84; 95% CI: 0.80-0.88; P<0.001]).

At week 24, however, there were no significant differences between patients treated with sacubitril/valsartan in median change in the 6-minute walk distance, with increases of 9.7 versus 12.2 m, respectively (adjusted mean difference: −2.5 m; 95% CI: −8.5 to 3.5; P=0.42). In addition, researchers observed no significant differences in mean change in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (12.3 versus 11.8; mean difference: 0.52; 95% CI: −0.93 to 1.97) or improvements in NYHA class (23.6% versus 24.0%; adjusted odds ratio: 0.98; 95% CI: 0.81-1.18).

Pieske and colleagues noted: “Unlike many other clinical trials, this study recruited only patients with reduced quality of life at screening. This approach was chosen because patients with lower quality of life may have more room for improvement. In line with this, large improvements from baseline in mean KCCQ scores were observed at week 24 in both treatment groups (with no significant differences between groups). However, because low KCCQ scores in patients with heart failure are often multifactorial, it may be that (similarly to 6-minute walk distance) further improvements in KCCQ are affected by persistent comorbidities.”

The most common adverse events in patients treated with sacubitril/valsartan compared with standard RAS inhibitor treatment or placebo included hypotension (14.1% versus 5.5%, respectively), albuminuria (12.3% versus 7.6%), and hyperkalemia (11.6% versus 10.9%).

“Sac/Valsartan was safe, well tolerated, and reduced elevated NTproBNP plasma levels (a marker of prognosis) more than standard therapies, but had no effect on submaximal exercise capacity,” concluded Pieske. “PARALLAX HF corroborates the notion that Sac/Val may exert beneficial effects in patients with HFrEF and HFpEF and extends this finding to different classes of comparators. The lack of benefit on exercise capacity was unexpected, but underlines the current discussion on the robustness of this test in HFpEF,” he added.

In their accompanying editorial, Margaret M. Redfield, MD, and Barry A. Borlaug, MD, both of the Mayo Clinic, Rochester, Minnesota, commended PARALLAX researchers on their well conducted trial.

“The study results documented a biological effect (reduction in NT-proBNP) to provide context for the observed effects on patient-centered outcomes. The trial also was well powered, used a comparator treatment group that is consistent with clinical use, included patients with mild reduction in LVEF (>40%), and used rigorous statistical approaches,” they wrote.

They also stressed the need for further studies.

“It is critical to study the effects of new therapies on symptoms, quality of life, and functional performance in patients with HFpEF. Older patients with HFpEF have many competing risks for hospitalization and mortality and thus, improvements in symptoms, quality of life, and physical function are arguably as or perhaps more valuable to some patients than are effects on risk of HF hospitalization or cardiovascular mortality,” wrote Redfield and Borlaug.

“Clinicians are eager to provide therapy to the large HFpEF population, and these therapies provide meaningful benefit on risk of HF hospitalization, an effect that will help offset the societal financial cost of these new therapies. However, clarity is required regarding which patients to treat, which drug or drug combinations to use, and most importantly, why to treat. Further studies are needed to inform such guidance, particularly studies to assess the effect of therapies on symptoms, quality of life, and ability to be active, which are often of the most importance to patients with HFpEF. In this regard, studies such as the PARALLAX trial provide clinically important information,” they concluded.

Study limitations include its short duration and lack of a run-in phase, stratification of comparator therapy based on the use of RAS inhibitor therapy before randomization, and exclusion of patients with BMI greater than 40.

  1. Compared with standard medical therapies, sacubitril/valsartan resulted in a significantly greater decrease in plasma N-terminal pro–brain natriuretic peptide at 12 weeks in patients with heart failure with preserved ejection fraction (HFpEF), according to results from the PARALLAX trial.

  2. Sacubitril/valsartan did not, however, improve submaximal exercise capacity at 24 weeks in patients with HFpEF.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was funded by Novartis Pharma AG.

Pieske reported receiving personal fees from Bayer, Bristol Myers Squib, Medscape, MSD, Novartis, and Servier and grants and personal fees from AstraZeneca.

Redfield and Borlaug reported no disclosures.

Cat ID: 3

Topic ID: 74,3,730,3,914,192,925